MXPA04006937A - Intermediates for preparing glycogen phosphorylase inhibitors. - Google Patents

Abstract

The instant invention provides novel processes and intermediates useful in the preparation of certain N-(indole-2-carbonyl)-beta-alaninamide compounds, which compounds are glycogen phosphorylase inhibitors useful in the treatment of diseases such as hypercholesterolemia, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertension, atherosclerosis, diabetes, diabetic cardiomyopathy, infection, tissue ischemia, myocardial ischemia, and in inhibiting tumor growth.

Description

INTERMEDIATES FOR THE PREPARATION OF GLUCOGEN PHOSPHORYLASE INHIBITORS FIELD OF THE INVENTION The present invention provides novel methods and intermediates useful in the preparation of certain N- (indole-2-carbonyl) -p-alaninamide compounds, said glycogen phosphorylase inhibitor compounds being useful in the treatment of diseases such as hypercholesterolemia, hyperglycemia , hyperinsulinemia, hyperlipidemia, hypertension, atherosclerosis, diabetes, diabetic cardiomyopathy, infection, tissue ischemia, myocardial ischemia, and in the inhibition of tumor growth.

BACKGROUND OF THE INVENTION Despite the early discovery of insulin and its extensive subsequent use in the treatment of diabetes, and the discovery and use of sulfonylureas (for example, Chlorpropamide ™ (Pfizer), Tolbutamide ™ (Upjohn), Acetohexamide ™ (El Lilly), Tolazamide ™ (Upjohn), and biguanides (for example, Phenformin ™ (Ciba Geigy) and Metformin ™ (GD Searle)) as oral hypoglycaemic agents, the therapeutic regimens for the treatment of diabetes remain unsatisfactory. , required in approximately 10% of diabetic patients in whom synthetic hypoglycemic agents are not effective (type 1 diabetes, insulin-dependent diabetes mellitus), requires multiple daily doses, usually by autoinjection. Insulin requires frequent estimates of blood or urine sugar levels, and administration of an excessive dose of insulin produces hypoglycemic lucemia, with effects ranging from mild abnormalities in blood glucose to coma, or even death. The treatment of non-insulin dependent diabetes mellitus (type 2 diabetes) usually consists of a combination of diet, exercise, oral agents, for example sulfonylureas and, in more severe cases, insulin. However, clinically available hypoglycaemic agents may have other side effects that limit their use. In any case, where one of these agents fails in an individual case, another can succeed. Clearly, it is clear that there is still a need for hypoglycemic agents that have fewer side effects or that are successful where others fail. Atherosclerosis, a disease of the arteries, is recognized as the leading cause of death in the United States and Western Europe. The pathological sequence leading to the development of atherosclerosis and occlusive heart disease is well known. The first phase of this sequence is the formation of "fatty streaks" in the carotid, coronary and cerebral arteries, and in the aorta. These lesions are yellow due to the presence of lipid deposits found mainly within the smooth muscle cells and in the macrophages of the intima of the arteries and the aorta. In addition, it is postulated that most of the cholesterol found within fatty streaks, in turn, induces the development of the so-called "fibrous plaques", which consist of accumulated smooth muscle cells of the intimate layer, loaded with lipids and surrounded by extracellular lipids, collagen, elastin and proteoglycans. These cells, plus the matrix, form a fibrous layer that covers a deeper deposit of cell debris and more extracellular lipids, consisting mainly of free and esterified cholesterol. The fibrous plaque forms slowly and, over time, is likely to calcify and necrose, advanced to the so-called "complicated lesion" that is responsible for arterial occlusion and the tendency toward mural thrombosis and spasms of the arterial muscle that characterize an advanced atherosclerosis. Epimediological evidence has firmly established hyperlipidemia as a primary risk factor in the induction of cardiovascular diseases (CVD) due to atherosclerosis. In recent years, medical professionals have placed a renewed emphasis on the reduction of plasma cholesterol levels, and in particular of cholesterol associated with low density lipoproteins, as an essential step in the prevention of CVD. Now it is known that the upper limits of the so-called "normal" cholesterol are significantly lower than what had been appreciated so far. As a result, it is now recognized that large segments of Western populations have a particularly high risk. Such independent risk factors include glucose intolerance, hypertrophy of the left ventricle, hypertension and being male. Cardiovascular disease prevails especially among diabetic subjects, at least in part due to the existence of multiple independent risk factors in this population. Therefore, the successful treatment of hyperlipidemia in the general population, and in diabetic subjects in particular, is of exceptional medical importance. Hypertension (high blood pressure) is a situation that occurs in human populations as a secondary symptom to various other disorders such as renal artery stenosis, pheochromocytoma or endocrine disorders. However, hypertension also manifests itself in many patients in whom the causative agent or disorder is unknown. Although such essential hypertension is often associated with disorders such as obesity, diabetes and hypertriglyceridemia, the relationship between these disorders has not been clarified. In addition, many patients have symptoms of high blood pressure in the complete absence of any other signs of disease or disorder. It is known that hypertension can directly produce cardiac, kidney failure and stroke, being all these conditions capable of producing death in the short term. Hypertension also contributes to the development of atherosclerosis and coronary heart disease, conditions that gradually weaken the patient and can lead, in the long term, to death.

The etiology of essential hypertension is unknown, although it is believed that several factors contribute to the onset of the disease. Among such factors are stress, uncontrolled emotions, an unregulated release of hormones (the renin system, angiotensin, aldosterone), an excess of salt and water due to poor kidney function, thickening of the walls and hypertrophy of the system vascular causing vascular constriction and genetic predisposition. The treatment of essential hypertension has been undertaken considering the above factors. In this way, a wide range of β-blockers, vasconstrictors, angiotensin-converting enzyme (ACE) inhibitors and the like have been created and marketed as antihypertensive agents. The treatment of hypertension using such agents has been beneficial in the prevention of short-term deaths such as heart failure, renal failure and cerebral hemorrhage (stroke). However, the development of atherosclerosis, or a heart disease due to hypertension for a long period of time, remains a problem. This implies that, although high blood pressure is reduced, the underlying cause of essential hypertension still lacks response to this treatment. Hypertension has been additionally associated with elevated levels of insulin in the blood, a condition known as hyperinsulinemia. Insulin, a peptide hormone whose main actions are to promote the use of glucose, protein synthesis and the formation and storage of neutral lipids, also acts, among other things, to promote the growth of vascular cells and increase renal sodium retention . These latter functions can be performed without affecting glucose levels and are known causes of hypertension. The growth of the peripheral vascular system, for example, can produce constriction of peripheral capillaries; while the retention of sodium increases the volume of blood. In this way, the reduction of insulin levels in hyperinsulinemic patients can prevent abnormal vascular growth and renal sodium retention caused by high insulin levels and, therefore, relieve hypertension. Cardiac hypertrophy is a significant risk factor in the development of sudden death, myocardial infarction and congestive heart failure. These cardiac events are due, at least in part, to the increased susceptibility to myocardial lesions after ischemia and reperfusion that can occur in both outpatients and perioperative situations. Currently there is an unmet medical need to prevent or minimize the adverse perioperative myocardial consequences, particularly perioperative myocardial infarction. Both cardiac and non-cardiac surgical operations are associated with substantial risks of myocardial infarction or death, and some seven million patients undergoing non-cardiac surgery are considered at risk, with incidences of perioperative death and complications. cardiac events as high as 20-25% in some cases. In addition, of the 400,000 patients who undergo coronary bypass surgery annually, it is estimated that perioperative myocardial infarction occurs in 5% and death in 1-2%. Currently there is no commercial drug therapy in this area that reduces damage to cardiac tissue due to perioperative myocardial ischemia or increases cardiac resistance to episodes of ischemia. It is foreseeable that such therapy will save lives and reduce hospitalizations, increase the quality of life and reduce the overall health costs of high-risk patients. The mechanism or mechanisms responsible for the myocardial lesions observed after ischemia and reperfusion is not fully understood; however, it has been reported (MF Allard, et al., Am. J. Physiol., 267, H66-H74 (1994) that pre-ischemic glycogen reduction is associated with better functional recovery of the left ventricle after ischemia in hypertrophied rat hearts Hepatic glucose production is an important target for the therapy of type 2 diabetes. The liver is the main regulator of plasma glucose levels in the post-absorption state (fasting), and the rate of hepatic glucose production in patients with type 2 diabetes is significantly higher than in normal individuals, similarly in the postprandial state (after eating), when the liver has a proportionately smaller role in the total supply of plasma glucose, the production of hepatic glucose is abnormally high in patients with type 2 diabetes.

Glycogenolysis is an important goal for the interruption of hepatic glucose production. The liver produces glucose by glycogenolysis (degradation of the glucose glycogen polymer) and gluconeogenesis (synthesis of glucose from 2 and 3 carbon atoms precursors). Several lines of evidence indicate that glycogenolysis can make an important contribution to the production of hepatic glucose in type 2 diabetes. First, in a normal man, in the post-absorption state, it is estimated that up to 75% of hepatic glucose production results from glycogenolysis. Secondly, patients who have hepatic glycogen storage diseases, including Hers disease (glycogen phosphorylase deficiency), present with episodic hypoglycaemia. These observations suggest that glycogenolysis can be a significant process for the production of hepatic glucose. Glycogenolysis is catalyzed in the liver, muscle and brain by Tissue specific soformas of the glycogen phosphorylase enzyme. This enzyme cleaves the macromolecule of glycogen by releasing glucose-1-phosphate and a new macromolecule of shortened glycogen. To date, two types of glycogen phosphorylase inhibitors have been published: glucose and glucose analogs [J. L. Martin et al., Biochemistry, 30, 10101 (1991)], and caffeine and other purine analogs [P. J. Kasvinsky et al., J. Biol. Chem., 253, 3343-3351 and 9102-9106 81978)]. It has been postulated that these compounds, and glycogen phosphorylase inhibitors in general, have a potential use for the treatment of type 2 diabetes by means of the reduction of hepatic glucose production and the reduction of glycaemia. See, for example, T. B. Blundell et al., Diabetology, 35, (Suppl 2), 569-576 (1992), and Martin et al., Supra. Recently, inhibitors of glycogen phosphorylase have been described in, among other documents, the publication of PCT International Patent Application No. WO 97/31901, and in commonly assigned US Patents Nos. 6,107,329, 6,277,877 and 6,297,269. United States patents granted under common grant Nos. 6,107,329, 6,277,877 and 6,297,269, the disclosures of which are hereby incorporated by reference in their entirety, describe novel substituted N- (indol-2-carbonyl) -p-alaninamide compounds, including 5-chloro-N - [(1S, 2R) -3- [3R, 4S] -3,4-dihydroxy-1-pyrrolidinyl] -2-hirox-3-oxo-1 - (phenylmethyl) propyl] -1 H-indole-2-carboxamide, hereinafter referred to as the compound of the formula (I); certain derivatives thereof; methods of treating diseases or conditions dependent on glycogen phosphorylase, by administering such compounds, such pharmaceutical compositions or such derivatives, to a mammal in need of such treatment. The present invention relates to improved methods useful in the preparation of the N- (indole-2-carbonyl) -p-alaninamides described in the aforementioned US Patents Nos. 6,107,329, 6,277,877 and 6,297,269, including 5-chloro-N - [(1S, 2R) -3- [3R, 4S] -3,4-dihydroxy-1-pyrrolidinyl] -2-hiroxy-3-oxo-1- (phenylmethyl) propiI] -1H-indole 2- carboxamide (I); certain intermediates related to it; and methods useful for the preparation of such intermediates. These improved methods, discussed in detail below, provide certain advantages over the methods described in the prior art mentioned above including, for example, less costs in the preparation of final products intended for human administration, minimization of impurities formed in the preparation of such final products and a reduced number of synthetic steps required during the preparation of such final products.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides novel methods and intermediates useful in the preparation of certain N- (indole-2-carbonyl) -p-alaninamide compounds, compounds which are inhibitors of glycogen phosphorylase useful in the treatment of diseases such as hypercholesterolemia, hyperglycemia, hyperinsulinemia. , hyperlipidemia, hypertension, atherosclerosis, diabetes, diabetic cardiomyopathy, infection, tissue ischemia, myocardial ischemia and in the inhibition of tumor growth.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel methods and intermediates useful in the preparation of certain N- (indole-2-carbonyl) -lalaninamide compounds. More particularly, the invention provides novel methods for preparing the compound 5-chloro-N - [(1 S, 2R) -3- [3R, 4S] -3,4-dihydroxy-1-pyrrolidinyl] -2-hiroxy-3 -oxo-1- (phenylmethyl) propyl] -1H-indole-2-carboxamide (I). The invention further provides intermediates useful in the preparation of the aforementioned compound and processes for the production of said intermediates. In one aspect of the invention, there is provided a process for preparing a compound of the structural formula (I) comprising the steps of: (a) coupling a compound of the structural formula (la) (la) with 3-pyrroline to provide an amide derivative of the structural formula (Ib) (ib); and (b) oxidizing the amide derivative (Ib) formed in step (a) to provide the compound of the structural formula (I). In the coupling reaction shown below in step (a), the compound of the structural formula (Ia) (the) prepared in accordance with the procedures described in the aforementioned US patents Nos. 6,107,329, 6,277,877 and 6,297,269, is coupled with 3-pyrroline to provide the compound of the structural formula (Ib) (Ib) Such coupling reaction can be carried out according to conventional synthetic methodologies known to one skilled in the art. For example, such coupling can be effected using an appropriate coupling reagent such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC), in the presence of 1-hydroxybenzotriazole (HOBT), 2-ethyloxy-1-ethyl oxy- carbonyl-1, 2-dihydroquinone (EEDQ), CDI / HOBT, propanephosphonic anhydride (PPA) or diethylphosphoryl cyanide and the like, in an inert aprotic reaction solvent, such as dichloromethane, acetonitrile, diethyl ether, tetrahydrofuran, optionally in the presence of a tertiary amine-based base, such as triethylamine or?,? '- düsopropylethylamine (Hunig's base). Such coupling is typically performed at a temperature ranging from about 0 ° C to about the reflux temperature of the solvent employed. In a preferred embodiment, the coupling reaction is performed at room temperature in tetrahydrofuran using EDC and a catalytic amount of HOBT, in the presence of an organic base selected from triethylamine or Hunig's base. The use of the Hunig base in such coupling is especially preferred. The 3-pyrroline starting material can be obtained from commercial sources. The oxidation reaction shown below in step (b) can be carried out according to synthetic methodologies known to one skilled in the art to convert olefins to c / 's-diols. Such oxidation can be carried out using ruthenium (III) chloride, with sodium periodate as a co-oxidant, AgO (J. Org. Chem., 61, 4801 (1996)), osmium tetroxide or a catalyst with N-methylmorpholine N-oxide ( NMO) in a polar organic solvent inert to the reaction such as acetonitrile, tetrahydrofuran, alkyl esters and the like. In a preferred embodiment, oxidation of (Ib) to compound (I) is performed using catalytic osmium tetroxide and N-methylmorpholine N-oxide (NMO) in tetrahydrofuran (Roserberg et al, J. Med. Chem., 33 , 1962 (1990)). The product of step (b) is then isolated, preferably according to methodologies well known to one skilled in the art. In another aspect, the invention provides a process for preparing a compound of the structural formula (I) (l) comprising the steps of: (a) coupling a compound of the structural formula (la) (the) with p-toluenesulfonate of (3aR, 6aS) -tetrahydro-2,2-dimethyl-4H-1, 3-dioxolo- [4,5-c] pyrrole (lv) (IVi) to provide an acetonide derivative of the structural formula (lia) ; and (b) cleaving the acetonide derivative (lia) formed in step (a) to give the compound of structural formula (I).

The coupling of the compound (Ia) with (IVi) to form the acetonide derivative (Na) can be carried out according to the procedures described hereinabove for the preparation of the compound (Ib). Preferably, the coupling is performed using EDC and HOBT in the presence of Hunig's base. The HOBT can be used catalytically, that is, in an amount less than one equivalent. Generally, a range of about 0.05 to about 0.50 equivalents may be employed in the coupling step; however, it is generally preferred that the HOBT be employed in a catalytic ratio of about 0.15 to about 0.25 molar equivalents of acid (la). Although acetonide (lia) may be employed directly in the subsequent cleavage step, it may occasionally be preferable, for reasons of color and purity improvement, to isolate the acetonide (lia) prior to said cleavage. The isolation of the less polar acetonide (lia) allows a purge of the more polar impurities and after the deprotection step, the more polar substrate (I) is isolated by crystallization, thus allowing a purge of the less polar impurities than they can be present. The conversion of the acetonide (lia) to the compound (I) can be carried out according to generally known procedures, for example by treatment of the isolated acetonide (lia) with a mineral acid, such as hydrochloric or hydrobromic acid, or an organic acid, such as methanesulfonic or p-toluenesulfonic acid, all in the presence of water.

Alternatively, the compound (I) can also conveniently be prepared by the production and in situ cleavage of acetonide (lia). The preparation of a solution of acetonide (Na) in a suitable solvent can be carried out as indicated above. The in situ conversion of the acetonide (Ha) to the compound (I), described in example 5 shown below, can also be conveniently carried out according to known procedures, for example by treatment of the acetonide (lia) solution with an acid aqueous mineral such as hydrochloric or hydrobromic acid, or an organic acid such as methanesulfonic acid or p-toluenesulfonic acid, also in aqueous conditions. The compound (I) thus produced can then be isolated according to known preparative procedures. In another aspect of the invention there is provided a process for preparing a compound of the structural formula (I) (I) A process comprising the steps of: (a) coupling a compound of the structural formula (I) of p-toluenesulfonate of c / s-3,4-dithyroxy-pyrrolidine (VI) ) HO OH H TsOH (Vi) to provide an ethanol solvate of the structural formula (Illa) He has) (b) desolvate the ethanol solvate (Illa) formed in step (a) to produce the compound of the structural formula (I). The coupling of the compound (a) to form ethanol solvate (Illa) can be carried out according to the coupling procedures previously described herein for the preparation of the compound (Ib) and the acetonide (lia). Preferably, the coupling is performed using EDC and HOBT in the presence of a tertiary amine base, such as triethylamine, or Hunig's base. The use of a Hunig base is especially preferred. The ethanol solvate (Illa) can be desolvated to form the compound (I) by dissolving (Illa) in an aprotic solvent, such as ethyl acetate or toluene, distilling the solution to remove the residual ethanol, treating the solution with water, that a concentration of water in the range of about 1% to about 3% is obtained, and heating the aqueous solution to the reflux temperature, at which point of crystallization (I) begins. Typically, the addition of seed crystals to the aqueous solution before reflux is preferred. The reflux period can comprise from a few hours to one or more days, preferably from about eight to about twenty hours. Once the crystallization is substantially complete the excess water is removed by azeotropic distillation, preferably at atmospheric pressure, and the suspension is then cooled to between about 5o and about 30 ° C, preferably at about room temperature, at which time the isolation of (I) is carried out according to conventional procedures, such as by filtration. In still another aspect, the present invention provides a process for preparing a compound of the structural formula (I) (or process comprising coupling a compound of the structural formula (Ia) (la) with a free base of c / s-3,4-dihydroxyprolidine (V) to provide the compound of the structural formula (I). The coupling of the compound (la) with the free base of c / s-3,4-dihydroxypyrrolidine (V) to form the compound (I) can also be carried out according to the coupling procedures previously described herein for the preparation of the compound (Ib), acetonide (Na) or ethanol solvate (Illa). The c / 's-3,4-dihydroxypyrrolidine free base (V) can be prepared according to the synthetic procedures described in detail below, including, for example, the procedure described in Example 18. The compound of Structural formula (I) thus prepared is then preferably isolated according to conventional methodologies which are well known to one skilled in the art. Another aspect of the invention provides synthetic methods useful for preparing the compound (V) and the acid addition salts thereof, compound or acid addition salts which are useful intermediates in the preparation of the compound (I). These exemplary synthetic methods are described in more detail in schemes 1 to 7 shown below. The p-toluenesulfonate salt of c / s-3,4-dihydroxypyrrolidine (Vi) can be obtained commercially. In one aspect, the invention provides a method useful in the preparation of the compound (V) or an acid addition salt thereof, which process comprises the steps indicated hereinafter in scheme 1.

SCHEME 1 (Va) (Vb) (V) As shown in scheme 1, the starting material 3-pyrrolidine (Aldrich Chemical Co., ilwaukee, Wl) is protected with BOC-anhydride in the presence of an organic or Bronested base in an aprotic solvent. The mixture of the protected products N-BOC-3-pyrrolidine (Va) can then be oxidized to the corresponding diol (Vb) according to known procedures for example, oxidation with osmium tetroxide, the use of catalytic osmium tetroxide with a co-oxidant, the use of ruthenium chloride (III) / sodium periodate (Shing, TKM, et al., Angew. Chem. Eur. J., 2, 50 (1996), or Shing, TKM, et al., Angew. Chem. Int. Ed. Engl., 33, 2312 (1994)), potassium permanganate, or reagents and similar conditions that are well known to one skilled in the art. The BOC protecting group of (Vb) can subsequently be removed by treatment with a suitable acid for example, trifluoroacetic acid, methanesulfonic acid and the like, in the presence of a reaction-inert solvent such as tetrahydrofuran, dichloromethane or acetonitrile, to form (V) . Preferably, the compound (V) is then isolated, in the form of the free base or in the form of an acid addition salt thereof, wherein said acid addition salt can be prepared according to known procedures. Said acid addition salts may include, for example, the addition salts of hydrochloride, hydrobromide, sulfate, acid sulfate, phosphate, acid phosphate, diacid phosphate, acetate, succinate, citrate, methanesulfonate (mesylate) and 4-methylbenzenesulfonate ( mesylate), (p-toluenesulfonate). Such acid addition salts can be easily prepared by reaction of the compound (V) with an appropriate conjugate acid. When the desired salt is of a monobasic acid (eg, hydrochloride, hydrobromide, tosylate, acetate, etc.), the acid form of a dibasic acid (eg, sulfate, succinate, etc., acids) or the diacid form of a tribasic acid (eg, diacids, phosphate, citrate, etc.), at least one molar equivalent and usually a molar excess of the acid is employed. However, when salts such as sulfate, hemisuccinate, phosphate or acid phosphate are desired, the appropriate and stoichiometric equivalent of the acid will generally be employed. The free base and the acid are usually combined in a co-solvent from which the desired acid addition salt is then precipitated or otherwise isolated by concentration of the mother liquor or by the precipitation effect resulting from the addition of a non-solvent. The especially preferred acid addition salts of the compound (V) comprise the addition salts of p-toluenesulfonate acids (Vi) and hydrochloride. An alternative process that can be used to prepare the compound (V), or an acid addition salt thereof, comprises the process indicated below in Scheme 2.

SCHEME 2 (Vb) and (Vla1) (vib) As shown in scheme 2, the starting material dibromodicyketone is reduced in the presence of a suitable reducing agent, such as sodium borohydride, in a reaction-inert solvent, such as ether ( tetrahydrofuran or methyl tert-butyl ether) or other suitable solvent (s) to provide a mixture of the sin- and anti- (Via) and (Via ') alcohols. The alcohols (Via) and (Via ') are then cyclized with benzylamine in the presence of a suitable base, such as sodium bicarbonate, yielding the diol (Vib). It has been shown that the use of an additive, such as potassium iodide, improves the rate of cyclization. See, for example, Larock Comprehensive Organic Transformations, VCH, New York, 337-339 (1989). The benzyl protecting group of (Vlb) can be subsequently removed by conventional procedures, such as hydrogenation using a catalyst such as palladium on carbon in a reaction-inert solvent, such as alcohol or ether, to form the compound (V), followed by the formation of acid addition salts, if desired.

Another alternative method that can be employed in the preparation of (V), or an acid addition salt thereof, comprises the process depicted in Scheme 3.

SCHEME 3 (Vllb) (Vlb) (V) In Scheme 3, meso-tartaric acid is cyclized with benzylamine to give the diol (Vllb). Such a deletion is typically carried out in a solvent inert to the reaction such as methylene chloride, tetrahydrofuran or ethyl acetate at a temperature generally higher than room temperature. See, for example, March, Advanced Organic Chemistry, 4th ed., Wiley Interscience, 420 (1992). It will be appreciated by one skilled in the art that such amide bond formations from carboxylic acids can be enhanced by the addition of coupling agents such as dicyclohexylcarbodiimide, N.N'-carbonyldiimidazole or 1,2-dihydro-2-ethoxy-1-quinolinecarboxylate of ethyl (EEDQ). The diol (Vllb) is then reduced to the diol (Vlb) by the use of known reducing reagents, such as lithium aluminum hydride, diborane, or sodium borohydride, in the presence of boron trifluoride.

The benzyl protecting group of (Vib) can then be removed by conventional procedures, such as hydrogenation using a catalyst such as palladium on carbon in a suitable solvent, such as an alcohol or ether, to form the compound (V), followed by formation of acid addition salts, if desired. Another method useful in the preparation of the compound (V), or an acid addition salt thereof, comprises the steps shown in scheme 4.

(Villa) (Vb) (V) In scheme 4, the butanotetraol starting material is converted to the diacetate (Villa) under conventional conditions such as treatment with hydrobromic acid and acetic acid, or by the procedures described in Talekar, DG, et al., Indian J. Chem. , Sect. B, 25B (2), 145-51 (1986), or Lee, E., et al., J. Chem. Soc, Perkin Trans. 1, 23, 3395-3396 (1999). The diacetate (Villa) is then cyclized with benzylamine in the presence of a suitable base such as sodium bicarbonate, to give (Vlb). As described above, the use of an additive such as potassium iodide to enhance cyclization may be employed, if desired or appropriate.

The benzyl protecting group of (Vib) can subsequently be removed by conventional procedures, such as hydrogenation, using a catalyst such as palladium on carbon in a suitable solvent such as an alcohol or ether, to form the compound (V), followed by the formation of acid addition salts, if desired. Another useful method in the preparation of (V), or an acid addition salt thereof, comprises the process shown in Scheme 5.

SCHEME 5 (Ka) (Vib) (In Scheme 5, (E) -1,4-dichloro-2-butene is dihydroxylated to produce the diol (IXa) using conditions known to one skilled in the art., for example hydrogen peroxide and formic acid, or m-chloroperoxy benzoic acid and water. The diol (IXa) is then cyclized with benzylamine in the presence of a suitable base, such as sodium bicarbonate, to give the diol (Vib). As described hereinabove, the use of an additive such as potassium iodide to enhance cyclization may be employed, if desired or appropriate. The benzyl protecting group of (Vlb) may subsequently be removed by conventional procedures, such as hydrogenation. using a catalyst such as palladium on carbon in a reaction-inert solvent, such as an alcohol or ether, to form the compound (V), followed by the formation of acid addition salts, if desired. Another method useful in the preparation of (V), or an acid addition salt thereof, comprises the process depicted in scheme 6.

SCHEME 6 (Ka) (Vlb) (V) In Scheme 6, (Z) -1,4-dichloro-2-butene is dihydroxylated to produce the diol (IXa) according to synthetic procedures known to one skilled in the art. For example, such oxidation can be performed using a mixture of sodium periodate and a ruthenium salt in an aprotic reaction-inert solvent such as acetonitrile or a halogenated hydrocarbon solvent such as chloroform, methylene chloride or carbon tetrachloride. When appropriate or desired, mixtures of solvents comprising aprotic solvents inert to the reaction can also be used, for example acetonitrile and ethyl acetate. In a preferred embodiment, the oxidation reaction is carried out using ruthenium chloride (III) hydride and sodium periodate in a cooled solvent mixture of acetonitrile / ethyl acetate. The diol (IXa) is then cyclized using benzylamine in the presence of a suitable base, such as sodium bicarbonate, to produce the diol compound (Vlb). As described hereinabove, the use of an additive such as potassium iodide for potential deletion can be employed if desired and / or appropriate. The benzyl protecting group of (Vlb) can be subsequently removed by conventional procedures, such as hydrogenation using a catalyst such as palladium on carbon in a suitable solvent, such as an alcohol or ether, to form the compound (V), followed by formation of acid addition salts, if desired. Another process for preparing the compound (V), or an acid addition salt thereof, comprises the process shown in scheme 7.

SCHEME 7 (Xla) (Xlb) (Vb) (V) As generally shown in Scheme 7, the aminodiol starting material is protected with BOC-anhydride in the presence of an organic or Bronested base in an aprotic solvent. The BOC protected diol (Xla) is then oxidized to dialdehyde (Xlb) by procedures generally known to one skilled in the art. For example, the diol (Xla) can be oxidized using a strong oxidizing agent such as potassium permanganate, ruthenium tetroxide, manganese dioxide or Jones reagent (chromic acid and sulfuric acid in water). Alternatively, the oxidation of (Xla) in (Xlb) can be performed by catalytic dehydrogenation using reagents such as copper chromite, Raney nickel, palladium acetate, copper oxide and the like. For further examples, see, for example, March, Advanced Organic Chemistry, 2nd edition, Wiley-lnterscience, 1992. The dialdehyde (Xlb) can then be cyclized to the BOC-protected diol (Vb) by coupling with pinacol. Known methods for effecting such coupling may comprise direct electron transfer using active metals such as sodium, magnesium or aluminum or by the use of titanium trichloride. The BOC group of (Vb) can then be removed by treatment with a suitable acid as described hereinabove. Preferably, the compound (V) is then isolated, in the form of the free base or in the form of an acid addition salt thereof, said acid addition salt being prepared as described above. Another aspect of the present invention provides synthetic methods useful for preparing the compound (IV) described below and the acid addition salts thereof, said compound and said intermediate acid addition salts also being useful in the preparation of the compound (I ). Said exemplary synthetic procedures are presented in detail in the schemes 8 to 10 shown below. In one aspect, the compound (IV), or an acid addition salt thereof, can be prepared according to the procedure shown in scheme 8.

SCHEME 8 (Xlla) (Xlib) (IVc) (IV) As shown in scheme 8, ribose is protected by formation of the acetonide derivative (Xlla) thereof. Such formation of acetonide can be carried out in a variety of ways, for example according to the procedures described in Greene, T.W., et al., Protective Groups in Organic Synthesis, 2nd edition, Wiley-lnterscience, (19919). As an example, the formation of the protected diol (Xlla) can be carried out using acetone in the presence of iodine. Oxidation of (Xlla) a (Xllb) can be performed using reagents, including sodium periodate in methanol. The reduction according to known procedures, for example by the use of lithium aluminum hydride or sodium borohydride in the presence of an acid such as acetic acid. The amine (IVc) is prepared by treating (Xllb) with benzylamine in methylene chloride or similar solvents inert to the reaction. The benzyl protecting group of (IVc) can be subsequently removed according to conventional procedures, such as hydrogenation, using a catalyst such as palladium on carbon in a suitable solvent, such as an alcohol or ether, to form the compound (IV). Preferably, the compound (IV) is then isolated, in the form of the free base or in the form of an acid addition salt thereof, said acid addition salt being prepared as described hereinabove. The preferred acid addition salts of the compound (IV) are the addition salts of p-toluenesulfonate acids (IVi) and hydrochloride. Another process for the preparation of the compound (IV), or an acid addition salt thereof, comprises the process represented in scheme 9. where Piv represents the pivaloyl residue, that is, (CHJ3) 3C (0) -. As shown in Scheme 9, mesoerythritol is protected using conventional methodologies to form the dipivaloyl derivative (XI). Such protection is preferably carried out using pivaloyl chloride in the presence of a strong organic base such as pyridine. The resulting diol (Xllla) can be protected by formation of the acetonide (Xlllb), by treatment of (Xllla) with acetic acid in acetone or by treatment with 2,2-dimethoxypropane (DMP). The Piv groups of (Xlllb) can be subsequently removed according to conventional procedures, for example those described in Greene, TW, et al., Protective Groups in Organic Synthesis, 2nd edition, Wiley-lnterscience, (1991), to form the derivative unprotected (Xlllc). As an example, deprotection of (Xlllb) can be carried out using a strong inorganic base, such as sodium or potassium hydroxide, in an aqueous solvent, such as an alcohol. Activation of the diol mesylate (Xlllc), in a suitable non-reactive solvent in the presence of a base such as triethylamine, gives the compound (Xllld). The delation of (Xllld) with benzylamine in the presence of a base, such as an organic amine, produces (IVc). The benzyl protecting group of (IVc) can be subsequently removed according to conventional procedures, such as hydrogenation, using a catalyst such as palladium on carbon in a suitable solvent, such as an alcohol or ether, to form the compound (IV). Preferably, the compound (IV) is then isolated, in the form of the free base or in the form of an acid addition salt thereof, said acid salt being prepared as previously described herein. In another aspect, the invention provides a generally preferred process for the preparation of the compound (IV), or the preferred p-toluenesulfonate acid addition salt (IVi) thereof, which process is depicted below in scheme 10.

SCHEME 10 The oxidation of N-benzylmaleimide to the diol (Vllb) can be carried out according to synthetic procedures known to one skilled in the art. For example, such oxidation can be performed using a mixture of sodium periodate and a ruthenium salt in an aprotic reaction-inert solvent such as acetonitrile, or a halogenated hydrocarbon solvent such as chloroform, methylene chloride or carbon tetrachloride. When appropriate or desired, mixtures of solvents comprising aprotic solvents inert to the reaction can also be used, for example acetonitrile and ethyl acetate. In a preferred embodiment, the oxidation reaction is performed using ruthenium chloride hydrate (III) and sodium periodate in a solvent mixture of acetonitrile / ethyl acetate below room temperature.

The formation of acetonide (IVb) can be carried out according to synthetic methodologies known to one skilled in the art. For example, said protection can be carried out by condensation of the diol (VI Ib) with acetone, 2,2-dimethoxypropane or a mixture of both, in the presence of an acid catalyst, such as sulfuric, p-toluenesulfonic or methanesulfonic acid. In a preferred embodiment, the protection reaction is carried out by condensing the diol (VI la) in 2,2-dimethoxypropane with a catalytic amount of methanesulfonic acid. The reduction of acetonide (IVb) to (IVc) can be carried out according to synthetic methodologies known to one skilled in the art. For example, such a reduction can be performed using a complex of boron or aluminum hydride including, for example, BH3THF, BH3eterate or Red-Al® (sodium (bis (2-methoxyethoxy) aluminum hydride); Aldrích Chemical Co., Milwaukee, Wl), in an aprotic solvent inert to the reaction, such as toluene or diethyl ether. In a preferred embodiment, the reduction of the protected acetonide (IVb) to (IVc) is carried out using Red-Al® in toluene. The deprotection of (IVc) can be carried out according to synthetic methodologies known to one skilled in the art. For example, using palladium salts or complexes, such as Pd (OH) 2 or Pd / C in polar protic solvents such as methanol or ethanol, in a non-protic solvent, such as tetrahydrofuran, or in a mixture of such solvents. Alternatively, said deprotection can be carried out under hydrogenation-transfer conditions, ie, pd / C with cyclohexene. In a preferred embodiment, the deprotection reaction is performed using Pd (OH) 2 / C in methanol. Preferably, the deprotected product (IV) is then isolated, in the form of the preferred p-toluenesulfonate acid addition salt (IVi) thereof, which may be prepared as previously described herein or commercially available.

Experimental part The present invention is illustrated with the following examples. However, it will be understood that the examples shown below in this document are provided solely for purposes of illustration and not limitation. The p-toluenesulfonate salt of c / s-3,4-dihydroxypyrrolidine (Vi) was purchased from Aldrich Chemical Co., Fine Chemicals Division, Milwaukee, Wl.

EXAMPLE 1 5-Chloro-N-rf 1 S, 2R) -3- (2,5-dihydro-1 H -pyrrol-1-yl) -2-hydroxy-3-oxo-1 - (phenylmethyl) propyl-1 H-indole-2-carboxamide (Ib) A sample of 5.00 g (0.0134 mmol) of acid (aR, S) -p - [[(5-chloro-1 H -indol-2-yl) carbonyl] amino] -a-hydroxybenzenebutanoic acid (la) (prepared in accordance with the procedures described in U.S. Patent Nos. 6,107,329, 6,277,877 and 6,297,269) and 3-pyrroline (1.1 g, 0.015 mmol) (Aldrich Chemical Co., ilwaukee, Wl) formed a suspension in 100 ml of tetrahydrofuran a a temperature of 20 to 25 ° C. The mixture was treated with 0.6 g, (0.33 equiv.). of 1-hydroxybenzotriazole hydrate (HOBT) and the mixture was cooled to 0 to 5 ° C. N, N-düsopropylethylamine (2.08 ml, 2.1 equiv.) Was added to the mixture for 15 minutes at 0-5 ° C. The mixture was then treated with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) (2.78 g, 1.1 equiv.) At a temperature between -10 and -6 ° C. The reaction was allowed to warm to about 20 ° C and was stirred at room temperature for about 24 hours. The reaction mixture was treated with water (50 ml) and ethyl acetate (50 ml), giving a biphasic mixture. The phases were pelleted and the organic phase was separated and concentrated to a solid by partial vacuum distillation. A total of 5.1 g (92.7% yield) of the pure title compound was isolated.

EXAMPLE 2 5-Chloro-Nr (1S, 2F0-3-f3R, 4Sl-3,4-dihydroxy-1-pyrrolidinin-2-hydroxy-3-oxo-1- (phenylmethyl) propyl-1 H-indole-2-carboxamide (l) A sample of 1.59 g (3.75 mmol) of (Ib), N-methylmorpholine N-oxide (413 mg, 3.52 mmol) and osmium tetroxide (3.6 g, 0.352 mmol) in 15 ml of tetrahydrofuran and the resulting mixture were combined. it was stirred overnight under a nitrogen atmosphere. The solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The phases were separated and the organic phase was washed twice with a sodium sulfite solution and then with sodium bicarbonate. The aqueous washings were washed again with ethyl acetate, dried over sodium sulfate, shaken with decolorizing charcoal and evaporated in vacuo. The residue was adsorbed on silica gel and subjected to flash chromatography eluting with ethyl acetate: methanol (9: 1). The fractions containing the product were combined, treated with decolorizing charcoal and evaporated to a foam that was triturated overnight with hexanes, yielding 505 mg (25% yield) of a tan solid. P. f. 150 ° -155! C.

EXAMPLE 3 5-Chloro-Nr (1S.2R) -2-hydroxy-3-oxo-1- (phenylmethyl) -3-rf3aR, 6aS) -tetrahydro-2,2-dimethyl-5H-1,3-dioxolor4, 5-Clpyrrole-5-illpropyl-1 H-indole-2-carboxamide (Ha) An amount of 25 g (0.067 moles) of (la) and (IV) (22.2 g, 0.0704 moles) was stirred in 125 ml of dichloromethane and 125 ml of tetrahydrofuran at a temperature of 20 ° to 25 ° C. . N.N-diisopropylethylamine (23.4 ml, 0.134 mol) was added to the mixture for 15 minutes at 20-25 ° C. The reaction solution was cooled between 0 and -10 ° C and treated with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) (14.2 g, 0.0741 mole) and hydroxybenzotriazole hydrate (HOBT) (10.0 g, 0.074 moles). The reaction mixture was stirred at -6 ° C to -10 ° C for about 30 minutes. The reaction was allowed to warm to room temperature for about 45 minutes and was stirred for about 2 hours. The reaction mixture was treated with 50% aqueous sodium hydroxide, giving a pH of about 10 and the biphasic mixture allowed to settle. The organic phase was concentrated to an oil by rotary evaporation using partial vacuum. A total of 31 g (88% yield) of the title compound was isolated.

EXAMPLE 4 f (1 S-Benzyl-3- (3R.4S) -dihydroxy-pyrrolidin-1-n- (2R) -hydroxy-3-oxopropylamide of 5-chloro-1 H acid -indole-2-carboxylic acid (I) A 2.0 g sample of acetonide (lia) was dissolved in a mixture of 10 ml of tetrahydrofuran and 10 ml of water. The pH was adjusted to 1.8 with 6N hydrochloric acid and the solution was heated to reflux. After heating to reflux overnight, the pH was adjusted to about 7-8 with 50% sodium hydroxide and the mixture was atmospherically distilled to remove the tetrahydrofuran. The phases were separated, the organic phase was washed with 10 ml of water and 25 ml of heptane were added to the combined organic phases. The resulting white crystalline precipitate was stirred for one hour, collected by filtration and washed with heptane. The solid was dried overnight under vacuum to provide 1.7 g of the title compound.

EXAMPLE 5 r (1 S-Benzyl-3 - ((3R, 4S) -dihydroxypyrrolidin-1-yn- (2R) -hydroxy-3-oxopropin-amide of 5-chloro-1 H-indole-2-acid carboxylic (I) A sample of 10 g (0.027 moles) of the (a), a sample of 8.88 g (0.028 moles) of (IVi) and 0.06 g (0.044 moles) of HOBT in 50 ml of tetrahydrofuran was combined and the resulting suspension was cooled to between -10 and -5 ° C. A total of 4.15 g (0.032 mole) of Hunig's base and 5.66 g (0.03 mole) of EDC was added and the resulting solution was stirred at room temperature for about 12 hours. The solution was diluted with 50 ml of water and the pH was adjusted to approximately 1.7 using 1.5 ml of concentrated HCl. The reaction mixture was then heated to reflux for about 10 hours. The pH was adjusted from 6.5 to 7.5 with 50% sodium hydroxide and the solution was reduced to a small volume by atmospheric distillation at a vessel temperature of about 90 ° C. A total of 100 ml of ethyl acetate was added, the organic phase was washed with 50 ml of water and diluted with 50 ml of toluene. The mixture was refluxed overnight, stirred for about 10 hours at room temperature and filtered. The residual solid was dried under vacuum at a temperature of about 45 ° C, yielding 10.4 g (86.6% yield) of the title product.

EXAMPLE 6 S-chloro-NK 1 S, 2R) -3-r3R.4S1-3.4-dihydroxy-1-pyrrolidinyl-2-hydroxy-3-oxo-1 - (phenylmethyl) propyl-1 H-indole ethanolate -2-carboxamide (Illa) (Illa) A 53 kg sample (142.2 moles) of (la) in 158.9 liters?,? - dimethylformamide was suspended. The resulting mixture was treated with ethyl acetate (317.8 liters) and cooled to 0 to 5 ° C. The cooled mixture was treated in order with α, β-diisopropylethylamine (36.6 kg, 284.3 moles), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (30 kg, 156.4 moles) and 1-hydroxybenzotriazole hydrate ( 24 kg, 156.38 moles). The reaction mixture was then treated with c / s-3,4-dihydroxypyrrolidine p-toluenesulfonate (Vi) (41.1 kg, 149.3 moles) and the reaction was allowed to stir for about 30 minutes at 0-5 ° C. Then, the reaction was warmed to room temperature and stirred for 6 hours. The reaction mixture was treated with water (794.5 liters), stirred for about 1 hour and then allowed to settle. The aqueous phase was removed by separation and washed twice with ethyl acetate (2 x 158.9 liters). The ethyl acetate phases were combined and washed three times with aqueous sodium bicarbonate (2 x 23.8 kg of sodium bicarbonate in 317.8 liters of water and 1 x 1 1.9 kg of sodium bicarbonate in 158.9 liters of water), the acetate solution of ethyl was combined with 90.8 liters of ethyl acetate and 158.9 liters of water, stirred for 30 minutes and then allowed to settle. The ethyl acetate phase was removed by separation, treated with decolorizing carbon (0.55 kg) and then stirred for about 15 minutes. The mixture was filtered to remove the carbon and the solution was concentrated in vacuo to a volume of approximately 363.2 liters. The ethyl acetate was distilled off using ethanol (4 x 249.7 liters), after which a thick white suspension was formed to a final volume of about 499.4 liters. The product was stirred at room temperature for approximately 18 hours. A total of 83.2 kg of title compound was isolated by filtration in the form of a wet ethanol cake.

EXAMPLE 7 r (1S-Benzyl-3 - ((3R, 4S) -dihicroxy-pyrrolidin-1-yl) - 5-chloro-1H-indole-2-carboxylic acid (2R) -hydroxy-3-oxopropylamide A 74 kg sample of (Illa) and 88 399.52 liters of ethyl acetate were combined and the resulting suspension was stirred at room temperature until a complete solution was obtained. The mixture was concentrated by atmospheric distillation until approximately 199.76 liters of distillate were collected (refractive index of distillate = 1.3716). A thick white suspension formed after cooling below 40 ° C. Water (6.1 I) was added to the suspension to form an almost transparent solution and then hexanes (245.16 liters) were added over a period of 2 to 3 hours. The resulting suspension was stirred at room temperature for about 2.5 days. The solids were removed by filtration, washed with ethyl acetate (36.32 liters) and then dried under a stream of nitrogen. The solid was dissolved in ethyl acetate and the solution was stirred at room temperature for about 1 1 days, after which a solid product gradually formed. The solid was then removed by filtration and dried under vacuum at 30-45 ° C, giving the title compound (30.9 kg, 71.6% yield) EXAMPLE 8 c / s-3,4-Dihydroxy-2,5-pyrrolidinedione (Vllb) (Vllb) A solution of N-benzylmaleimide (50.0 kg), in 125 I of acetonitrile and 859 I of ethyl acetate was combined with an aqueous mixture of 0.499 kg of ruthenium chloride hydrate (III) in 352 I of water, and the resulting reaction mixture was cooled to about 5 ° C. Sodium periodate (74.4 kg) was added with stirring to the reaction solution in small portions, while maintaining the reaction temperature between 3 ° C and 5 ° C. once the addition was complete, the reaction was quenched with an aqueous solution of sodium thiosulfate (45 kg) in 38 l of water and the resulting suspension was granulated for about 20 minutes. The inorganic salts were removed by suction filtration and the filter cake was washed with ethyl acetate. The combined filtrates were washed with water and allowed to settle. The aqueous phase was extracted with ethyl acetate and the organic phases rich in product were combined and washed with a solution of 8 kg of sodium chloride in 72 l of water. The organic extracts were concentrated by atmospheric distillation at a temperature of about 75 ° C, cooled to room temperature and allowed to granulate for 2-4 hours. The suspension was cooled (5 ° C-15 ° C) and hexane (360 I) was added and granulation was continued for about 1 hour. The precipitated solids were collected by suction filtration, washed well with ethyl acetate followed by hexane and then dried under vacuum at a temperature of about 40 ° C to about 45 ° C to provide the title compound (42.2 kg, 71%) in the form of a white solid.

EXAMPLE 9 (3aR.6aS) -Dihydro-2-dmethyl-5-phenylmethyl-4H-1,3-dioxolor4.5-clpyrrole-4.6 (5H) -dione (IVb) To a 58.6 kg suspension of (IVa) in 17.2 I of 2,2-dimethoxypropane was added 1.72 I of methanesulfonic acid and the reaction mixture was stirred at room temperature for 6 to 9 hours until the reaction was complete. A total of 322 I of diisopropyl ether was added to the reaction mixture and the resulting suspension was granulated. After cooling to a temperature of -10 ° to -15 ° C, the granulation was continued for a further 2 hours. The precipitated solids were collected by filtration, washed with diisopropyl ether and dried under vacuum for about 12 hours at a temperature of 40 ° to 45 ° C, affording the title compound (57.8 kg, 84% yield) EXAMPLE 10 (3aR, 6aS) -Tetrahydro-2,2-dimethyl-5- (phenylmethyl-4H-1,3-dioxolor4.5-clpyrrole) (IVc) A total of 56.1 kg of (IVb) and 563 I of toluene was combined and the mixture was heated to a temperature between 50 ° C and 60 ° C until an almost complete solution was achieved. The resulting solution was filtered to remove some traces of insoluble material and then added to a solution of 277.6 kg of Red-AL® (65% by weight solution of bis (2-methoxyethoxy) aluminum hydride in toluene) in 141 I of toluene The resulting solution was heated to reflux for about 4 hours and then cooled to about room temperature. To the reaction solution was slowly added a solution of 224 I of a 50% aqueous solution of sodium hydroxide in 623 I of water, while carefully maintaining an internal temperature between 10 ° C and 30 ° C. After the addition, the mixture was stirred for approximately 20 minutes and the phases allowed to settle. The organic phase was washed twice with portions of 335.96 liters of water, dried and the toluene was removed by atmospheric distillation, displacing it with methanol. The resulting oil (93% yield) was used directly in the next step.

EXAMPLE 11 (Alternative preparation) (3aR, 6aS) -Tetrahydro-2,2-dimethyl-5- (phenylmethyl) -4H-1,3-dioxolo-r4,5-c1pyrrole (IVc (IVc) A solution of 47.5 kg of (IVb) in 378.2 I of tetrahydrofuran was concentrated to about ¾ of its volume by distillation, cooled and sampled for water content. While maintaining a temperature between 10 ° C and 20 ° C, a total of 263 kg of borane-tetrahydrofuran complex (2M in tetrahydrofuran) was added under a nitrogen atmosphere at a rate of about 1.0 kg / minute. The reaction mixture was allowed to stir at room temperature for about 4 hours, time after which the reaction was stopped by the addition of 238.5 ml of methanol while maintaining a temperature of 10 ° C and 20 ° C during the addition. After addition of methanol, the mixture was stirred for about 1 hour at room temperature, then at 35 ° -45 ° C for about 2 hours and then at reflux temperature, at which time the tetrahydrofuran was displaced with methanol, concentrating the reaction mixture to about 145 I by atmospheric distillation at a temperature of 55 ° C to 65 ° C. The mixture was cooled to 30 ° C and 50 ° C, 473 I of methanol was added and the mixture was concentrated to a final volume of about 145 I again by atmospheric distillation as described above, the concentrate was cooled to about room temperature and about 1 liter of water was added. The resulting solution of the title compound was used directly in the next step.

EXAMPLE 12 p-Toluenesulfonate of (3aR, 6aS) -tetrahydro-2l2-dimethyl-4H-1,3-dioxolo- (IVi) A 195 I sample of (IVc) was combined in a hydrogenation vessel with 7.1 kg of 20% palladium hydroxide on carbon (moistened with 50% water) and the mixture was hydrogenated at about 344.73 kPa for about 10 hours at approximately 20 ° C.

After completion of the reaction, the mixture was filtered to remove the catalyst and the filter cake was washed well with methanol. The reaction mixture was concentrated by atmospheric distillation to a volume of about 80 I and 288 I of methyl ethyl ketone was added, the solution was reduced in volume to about 133 I by atmospheric distillation and the solution was filtered. The resulting solution was then treated for a period of about 1 hour with a solution of 34.6 kg of p-toluenesulfonic acid in 102 I of methyl ethyl ketone and the mixture was allowed to granulate for about 5 hours at 10 ° C-20 ° C. The suspension was cooled to between 0 ° C and 5 ° C and granulated for a further 2 hours. The precipitated product was collected by filtration, washed with cold methyl ethyl ketone and dried under vacuum at 40 ° C-45 ° C, yielding the title compound (44.8 kg, 74% yield) as a white crystalline solid.

EXAMPLE 13 3,4-O-lsopropylidene-D-ribofuranose (Xlla) (Xlla) To a 500 ml flask equipped with a magnetic stir bar was added D-ribose (20.0 g, 0.13 mol). Acetone (200 ml) was added and stirring was started. Iodine (0.01 g, 0.40 mmol) was added and the solution was stirred at room temperature until a clear brown solution was obtained. Sodium thiosulfate (0.50 g, 3.16 mmol) was added and the suspension was stirred until the solution became colorless. Diatomaceous earth (5.00 g) was added to the suspension and the mixture was filtered. The filtrate was concentrated in vacuo to yield 25.0 g (99% yield) of the title compound as a thick yellow oil, which was used directly without further purification. Thin-layer chromatographic analysis (ethyl acetate, silica gel, visualized with phosphomolybdic acid) showed four spots: Rf = 0.89, 0.72 (main product), 0.38 and 0.00. 1HRMN (300MHz); d 6.47 (d, 1 H), 5.32 (d, 1 H), 4.96 (t, 1 H), 4.82 (d, 1 H), 4.53 (d, 1 H), 4.32 (m, 1 H), 3.64 (m, 2H), 1.48 (s, 3H), 1.32 (s, 3H).

EXAMPLE 14 3,4-0-lsopropylidene-2-hydroxy-5-methoxyfuran (Xllb) (Xllb) To a three-necked flask equipped with a reflux condenser, mechanical stirrer and a temperature controller were added (Xllla) (20.0 g, 0.11 mol) and anhydrous methanol (500 ml). The stirred reaction mixture was then placed under a nitrogen atmosphere. Sodium periodate (44.8 g, 0.21 mol) was added and the stirred mixture was heated to about 40 ° C overnight. The solution was allowed to cool to room temperature, diatomaceous earth (10 g) was added and the suspension was filtered. The resulting filtrate was concentrated to a thick oil which was dissolved in 300 ml of methylene chloride. The resulting filtrate was washed successively with saturated aqueous sodium bicarbonate (200 ml), 2% aqueous sodium thiosulfate (200 ml) and saturated aqueous sodium chloride (200 ml). The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to afford 13.2 (66% yield) of the title compound as a yellow oil. This material was used directly without further purification. Thin layer chromatographic analysis (1: 1 of lime acetate / hexanes, silica gel, visualized with phosphomolybdic acid) showed two spots: Rf = 0.82, 0.66 (main product). 1 H NMR (300 MHz; CDCl 3) [diastereomeric mixture]: d 5.43 (2s), 5.41 and 5.28 (2d), 5.05 (s, 1 H), 4.85 (s, 1 H), 4.68 (m, 1 H), 3.98 and 3.98 (s), 3.43 (s, 3H), 3.36 (s, 3H), 1.53 (s, 3H), 1.38 (s, 3H), 1.47 (s, 3H), 1.32 (s, 3H).

EXAMPLE 15 cis-3,4-Q-lsopropylidene-N-benzylpyrrolidine flVc) (IVc) Methylene chloride (400 ml) was charged to a three-necked flask equipped with an addition funnel, pressure guage, mechanical stirrer and thermometer. Sodium borohydride (7.20 g, 0.19 mol) was added, stirring was started and the suspension was cooled to about 5 ° C with an ice bath. Acetic acid (37.1 g, 0.62 mol) was added dropwise over approximately 45 minutes. The cooling bath was then removed and the reaction mixture was allowed to warm to room temperature, at which time it was allowed to stir for about two hours. Benzylamine (7.10 g, 0.07 mol) was added, followed immediately by the addition of a solution of (Xllb) (12.0 g, 0.63 mol) in 30 ml of methylene chloride. The solution was stirred overnight at room temperature. The reaction was quenched with a saturated aqueous solution of sodium bicarbonate (200 ml) and the resulting biphasic mixture was stirred vigorously for approximately thirty minutes. The organic phase was separated and the aqueous phase was extracted with methylene chloride (200 ml). The combined organic extracts were washed successively with saturated aqueous sodium bicarbonate (200 ml) and 10% aqueous sodium chloride (200 ml). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. This yields 14.5 g (98.6% yield) of the title compound in the form of a yellow oil. Thin-layer chromatographic analysis (20% ethyl acetate / hexanes, silica gel, visualized with phosphomolybdic acid) showed two spots: Rf 0.36 (main product), 0.02. 1 H NMR (300 MHz; CDCl 3) d 7.2-7.4 (m, 5H), 4.65 (d, 2H). 3.62 (s, 2H), 3.06 (d, 2H), 2.17 (dd, 2H), 1.58 (s, 3H), 1.32 (s, 3H).

EXAMPLE 16 c / s-3,4-dihydroxy-N-benzylpyrrolidine hydrochloride (VI b) (Vlb) To a round bottom flask equipped with a reflux condenser and a magnetic stir bar was added (IVd) (5.00 g, 0.02 mol). Ethanol (10 ml) was added and stirring was started. Concentrated hydrochloric acid (7 mL, 0.09 mol) was added and the solution was heated to reflux. After about four hours, the solution was allowed to cool to room temperature and concentrated in vacuo, yielding a thick oil. Ethanol (10 mL) was added and the resulting solution was stirred at room temperature. Isopropyl acetate (35 ml) was added dropwise resulting in crystallization of the product. The suspension was stirred overnight, filtered and the filter cake was washed with isopropyl acetate (20 mL). The filter cake was dried overnight at room temperature under reduced pressure (about 30 mm Hg), yielding 2.7 g (56% yield) of the title compound as an off-white solid, e.g. F. 122-123 ° C. 1 H NMR (300MHz; CDCI3): d 7.58 (m, 2H), 7.45 (m, 3H), 5.48 (day, 2H), 4.38 (d, 1 H), 4.32 (sa, 2H), 4.25 (sa, 1 H), 4.08 ( sa, 1 H), 3.42 (m, 1 H), 3.32 (m, 2 H), 3.13 (m, 1 H), 3.02 (m, 1 H).

EXAMPLE 17 c / s-3,4-Dihydrox8pyrrolidine (v) HO OH H (V) A 3.34 kg (Vlb) sample was dissolved in 1.81 ethyl acetate and added to a mixture of 669 g of 10% Pd / C (moistened with 50% water) in 40.86 liters of methanol. The resulting mixture was hydrogenated with stirring at a pressure of about 344.75 kPa for about 73 hours. The catalyst was removed by filtration and concentrated in vacuo to 1.98 kg of a thick amber oil that partially crystallized. To the oily residue was added about 2 l of isopropanol, and the suspension was distilled azeotropically to remove residual traces of water, resulting in the collection of approximately 1 l of distillate. 1 I of isopropanol was added and the resulting suspension was stirred at room temperature for about 48 hours. The mixture was filtered, the collected solid was washed with 420 ml of isopropanol and the product was dried in vacuo at room temperature, yielding 826 g of the title free base as a hygroscopic white solid, e.g. F. 108 ° -119 ° C. An additional 97 g of product were obtained from the concentrated filtrate. H NMR (DMSO-d6): d: 2.46-2.51 (m, 2H, 2? 5?), 2.81-2.87 (m, 2H, 2"H, 5" H), 3.30 (ss, 1 H, 1 -NH), 3.74-3.77 (m, 2H, 3-H, 4-H), 4.39 (sa, 2H, both OH). 13 C NMR (DMSO-de): d 52.62, 71.93. Analysis calculated for C4H9N02: C, 46.59; H, 8.80; N, 13.58. Found: C, 46.62; H, 9.36; N, 13.43.

EXAMPLE 18 5-Chloro-N-r (1S, 2R) -3-f3R, 4S1-3. 4-Dihydroxy-1-pyrrolidinin-2-hydroxy-3-oxo-1- (phenylmethyl) propyl-1 H-indole-2-carboxamide (I) (An amount of 3.05 kg (la) was dissolved in a mixture of 6.1 I of dimethylformamide and 18.16 liters of ethyl acetate.The reaction solution was cooled to between 0 and 5 ° C and treated with hydroxybenzotriazole hydrate (HOBT) (1.38 kg), followed by 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) (1.72 kg) While maintaining the internal temperature at approximately 5 ° C, they added 884.4 g of free cis-3 base , 4-dihydroxypyrrolidine (V) and the reaction was allowed to stir at room temperature for about 15 hours.The reaction was then filtered to between 10 ° and 15 ° C and was slowly quenched with 39 I of water. The lower layer was removed and the aqueous layer was then washed with approximately 9.08 liters of ethyl acetate.The organic and product phases were combined and washed three times with sodium bicarbonate solutions (one wash with a 1.37 kg sodium bicarbonate solution). in 18.16 liters of water , followed by two washes with a solution of 687 g of sodium bicarbonate in 9.08 liters of water). The organic phase was treated with decolorizing carbon, filtered and the residue was washed with 4.54 liters of ethyl acetate. The filtrate was concentrated to a volume of about 9.08 liters, diluted with 16 I of ethanol and then concentrated in vacuo to a volume of about 8 I. An additional 10 I of ethanol was added and the resulting suspension was stirred overnight. An additional 10 I of ethanol was added and the mixture was filtered. The collected solid was washed with 3 I of ethanol and dried under vacuum at a temperature of about 35 ° C, yielding 2.47 kg of the title compound. Having described the invention as above, the contents of the following are declared as property:

Claims (2)

NOVELTY OF THE INVENTION
1. CLAIMS 1.- A compound of the structural formula
2. 2.- A compound of the structural formula